Compositions and methods of making rapidly dissolving ionically masked formulations

ABSTRACT

The present invention includes compositions and methods for reduce the taste of the drug in the drug resin complex. The composition may include one or more drug-resin complexes and a highly compressible, free-flowing pharmaceutical excipient. The resin is present in an amount effective to reduce the taste of the drug in the drug resin complex relative to an otherwise identical pharmaceutical composition without the resin; and wherein the highly compressible, free-flowing pharmaceutical excipient causes release of the drug-resin complex in the mouth.

FIELD OF INVENTION

The invention relates to compositions and methods of making rapidlydisintegrating or chewable, sustained-release formulations, and moreparticularly, to compositions and methods for making rapidlydisintegrating ionically masked formulations.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with ionically masked pharmaceutical agents that arerapidly disintegrating and delivered in an extended or sustained-releaseform, as an example.

Methods for sustained release are known in the art. One such method ofmaking sustained release particles is taught in U.S. Pat. No. 6,120,787,issued to Gustafsson, et al., which teach a method for preparingparenterally administrable sustained release microparticles. The methodincludes preparing core particles in an aqueous medium that isessentially free from organic solvent and the biologically activesubstance is entrapped therein during or after preparation, e.g., dryingthe core particles. The coating may be the same release-controllingpolymer, which is added by an air suspension technique to create a shellon the core particles without any detrimental exposure of the activesubstance to organic solvent.

Another sustained-release composition includes an amorphous polymer astaught in U.S. Pat. No. 6,613,358, issued to Randolph, et al., whichprovides for a sustained release composition of a pharmaceuticalsubstance that includes: a biocompatible polymer that is highlyamorphous and a pharmaceutical substance in a hydrophobic ion complexwith an amphiphilic material. A compressed antisolvent method formanufacturing the composition it also taught, as are various productforms incorporating the composition and various uses for thecomposition.

Yet another sustained release drug formulation is taught in U.S. Pat.No. 5,980,945, issued to Ruiz in which a sustained release drugformulation includes a drug; a biodegradable polymer that is insolublein water; and an oil vehicle in which both the drug and the polymer aredissolved. The oil vehicle may contain 10-100% by volume of apharmaceutically acceptable oil and 0-90% by volume of apharmaceutically acceptable liquid carrier for the drug or the polymer.

Finally, U.S. Pat. No. 5,674,533 issued to Santus, et al., teachespharmaceutical compositions for the controlled release of theanti-tussive, moguisteine, in a liquid suspension designed either asready-to-use and time-stable liquid formulations with a shelf-life of atleast two years, or as dry formulations that are reconstituted withwater when needed and then remain stable throughout the treatmentperiod. Santus teaches the use of coated microgranules for thecontrolled release of moguisteine having sizes ranging from 50 to 500μm, preferably from 90 to 300 μm, which are capable of remaining easilyin suspension in a liquid for extended times. The microgranules have amoguisteine core, with one or more optional plasticizers and excipients,granulated into microgranules having sizes smaller than 500 μm, uniformsurfaces, substantially spherical shapes, apparent densities of about500 to 600 g/l and very low friabilities, which are made by wet-kneadingmicronised moguisteine using water or a mixture of water and othersolvents. These initial microgranules have controlled-release propertiesby, a first coating having essentially hydrophilic characteristics,which isolates the microgranules; followed by a second coating havinglipophilic characteristics on top of the first coating; and a thirdcoating having hydrophilic characteristics.

Orally administered drug formulations may be provided to the patient inmany dosage forms, including solid forms (e.g., capsules, caplets,effervescent or tablets) and liquid forms (e.g., solutions, syrups,emulsions or suspensions). Generally, orally administered drugformulations administered in solid dosage form are intended to beswallowed whole and any disagreeable taste can be easily masked with anexterior coating. However, some formulations are designed for rapidabsorption of the active ingredient through the oral mucosa, e.g.,chewing of the tablets, effervescent, and the like and thus result intastes that are more difficult to mask. A growing market for these andother products is the pediatric and geriatric patients.

Many pharmaceutical compositions must be formulated as liquids for useby pediatric, geriatric patients, disabled persons, incapacitatedpatients and persons with dysphagia often have trouble swallowing. Toalleviate this challenge a number of drug delivery protocols have beendeveloped including rapid in-mouth disintegrating tablets, tablets whichdisintegrate in liquid prior to ingestion, liquids and syrups, gums andtransdermal compositions. Unfortunately, these delivery methods can posetheir own problems.

For example, immediate release compositions with rapid absorption of theactive ingredient through the oral mucosa (e.g., rapid in-mouthdisintegrating tablets, tablets that disintegrate in liquid prior toingestion, liquids and syrups, gums) may have an unpleasant texture oreven an unpalatable taste associated with the immediate release agent orother component of the composition.

SUMMARY OF THE INVENTION

The present inventors recognized that certain drugs produce anunpalatable taste associated with the immediate release agent that arenot effectively masked by traditional taste masking techniques. Thepresent invention addresses the problems associated with the delivery ofone or more active agents in a solid dosage form under controlledconditions. Solid, chewable formulations are often preferred by manyusers due to the easy of delivery, namely, natural chewing andswallowing thereby leading to increased compliance with dosing regimens.Many children and adults fail to comply with dosing instructions due tothe size, shape, taste and/or mouth-feel of, e.g., tablets, caplets andeven gelcaps.

The present inventors further recognized that delivery of agents in achewable formulation is not always preferred by users because of thetaste and/or mouth feel of the active agents and/or excipients oftenincluded with chewable formulations. What is needed are formulationsthat are manufactured using commonly used equipment, are shelf-stablehave improved mouth-feel (e.g., less grainy, bitter or slimy) andprovide actual controlled, sustained, mixed or modified release.Finally, it was recognized that despite many decades of research anddevelopment, controlled-release formulations have not been amenable tolarge-scale production in facilities and to amounts that are permissiblefor industrial applicability of controlled-release chewableformulations. However, despite the many known techniques for eliminatingthe problems commonly associated with the manufacture of chewableformulations, and hence their widespread failure, none of theseformulations have solves the problems of patient compliance due to tasteand mouthfeel.

More particularly, the present invention includes compositions andmethods for preparing a chewable, controlled-release formulation byblending one or more controlled release microbeads having one or moreactive agents with one or more microbeads. The one or more microbeadsmay include an enteric coat, a resin coat, a lacquer coat, apH-sensitive coating, a biodegradable polymer matrix, a water solublematrix, an ionic matrix, combinations and mixtures thereof. The one ormore microbeads may also include one or more polymers selected fromcellulose, ethylcellulose, methylcellulose, propylcellulose,methoxypropylcellulose, cellulose nitrate, poly(vinyl alcohol),poly(vinyl chloride), polystyrene, polyethylene, polypropylene,poly(ethylene-co-vinyl acetate), poly(hydroxybutyric acid),poly(hydroxyvalerianic acid-co-hydroxybutyric acid), poly(lactic acid),poly(glycolic acid), poly(lactic acid-co-glycolic acid),poly(ε(-caprolactones), poly(c-caprolactone-co-DL-lactic acid),poly(maleic anhydride), polyamides, gelatin, chitosan, collagen,poly(hydroxyalkyl)-L-glutamines, poly(γ-ethyl-L-glutaminate-co-glutamicacid), poly(L-leucine-co-L-aspartic acid), poly(proline-co-glutamicacid), poly(alkyl 2-cyanoacrylates), polyurethanes, poly(methylmethacrylate), poly(methyl methacrylate-co-methacrylic acid) andpoly(methacrylate-co-hydroxypropyl methacrylate), polystyrene,polistirex, polacrilex and salts, combinations and mixtures thereof.

The present invention may be, e.g., a taste-masked soluble chewablepseudoephedrine and chlorpheniramine pharmaceutical composition. Thecomposition includes a pseudoephedrine-resin complex, achlorpheniramine-resin complex and one or more amorphous sugars. Thecomposition may be a compressible, free-flowing, pharmaceutical,taste-masking excipient, wherein the highly compressible, free-flowingpharmaceutical excipient aids the release of the drug-resin complex inthe mouth.

The present invention provides a method of masking the taste of arapidly disitegrating or chewable, taste-masked pharmaceuticalcomposition by adding one or more amorphous sugars to a pharmaceuticallyactive drug-resin complex. A taste-masked soluble chewable compositionmay include pseudoephedrine and chlorpheniramine in a therapeuticallyeffective amount formed into a pharmaceutical composition. Thecomposition may include a pseudoephedrine-resin complex, achlorpheniramine-resin complex, one or more amorphous sugars and acompressible, free-flowing, pharmaceutical, taste-masking excipient. Thepseudoephedrine and the chlorpheniramine are slowly released as thecomposition is chewed. The composition becoming thixotropic when chewedbut not fully dissolving for at least 10 seconds, so as to dissolvethereafter in saliva during chewing.

The present invention includes a rapidly dissolving, taste-maskedhyoscyamine pharmaceutical composition. The composition includes ahyoscyamine-resin complex, one or more amorphous sugars and acompressible, free-flowing, pharmaceutical, taste-masking excipient. Thehyoscyamine is released slowly when the tablet disintegrates or ischewed. The rapidly disintegrating, taste-masked pharmaceuticalcomposition may include any salt of hyoscyamine, e.g., an ionicallybound hyoscyamine. The composition may be a hyoscyamine-resin complexand one or more amorphous sugars. The hyoscyamine is released slowlywhen the composition is chewed, the composition becoming thixotropicwhen chewed but not fully dissolving for at least 30 seconds whenchewed, and the composition slowly dissociates when chewed, tosubstantially dissociate thereafter in saliva during chewing.

The present invention includes a chewable tablet in which apharmaceutically active drug-resin complex is slowly released when thetablet is chewed. As the tablet is chewed it becomes thixotropic but notfully dissociated for at least 10 seconds. The tablet may slowlydissociate thereafter in saliva during chewing or once swallowed for upto 24 hours. The chewable formulation may include a portion of the oneor more beads with an immediate release profile and another portion witha controlled or delayed release profile. In one example, the activeagent may be included in two different salt forms or on two differentresins, wherein the active agent is differentially released or becomesdissolved and/or bioavailable at a different rate from the second saltor released from the second bead. When using an ion-exchange matrix,bead or resin to retain the one or more active agents the liquidsolution will in some cases be a low-ionic strength, depending on thenature of the ion-exchange matrix and the one or more active agents.Based on the present disclosure, the skilled artisan may easilydetermine the best matrix for a particular active, determine the amountof loading (theoretical and empirical), and the conditions for retentionand release.

Examples of active agents that may be provided as part of the chewableformulations of the present invention include vitamins, minerals,nutritional supplements, herbal extracts, gums, gels, oils, salts,mixtures and combinations thereof. Pharmaceutical active agents mayinclude, e.g., protein, peptide, carbohydrate, polysaccharide,glycoprotein, lipid, hormone, growth factor, cytokine, interferon,receptor, antigen, allergen, antibody, antiviral, antifungal,antihelminthic, substrate, metabolite, cofactor, inhibitor, drug,nutrient, toxin, poison, explosive, pesticide, chemical warfare agent,biowarfare agent, biohazardous agent, infectious agent, prion,radioisotope, vitamin, heterocyclic aromatic compound, carcinogen,mutagen, narcotic, amphetamine, barbiturate, hallucinogen. In some casesthe chewable may be, eg., a vaccine for against a virus, bacterium,helminth and/or fungi, fragments, receptors or toxins thereof, e.g.,Salmonella, Streptococcus, Brucella, Legionella, E. coli, Giardia,Cryptosporidium, Rickettsia, spore, mold, yeast, algae, amoebae,dinoflagellate, unicellular organism, pathogen, cell, combinations andmixtures thereof. The one or more active agents may be a pharmaceuticalagent, an enzyme, a cytokine, a growth promoting agent, an antibody, anantigen, a hormone, a vaccine, a cell, a live-attenuated pathogen, aheat-killed pathogen, a virus, a bacteria, a fungi, a peptide, acarbohydrate, a nucleic acid, a lipid, mixtures and combinationsthereof.

Specific examples of active agents include: steroids, respiratoryagents, sympathomimetics, local anesthetics, antimicrobial agents,antiviral agents, antifungal agents, antihelminthic agents,insecticides, antihypertensive agents, antihypertensive diuretics,cardiotonics, coronary vasodilators, vasoconstrictors, β-blockers,antiarrhythmic agents, calcium antagonists, anti-convulsants, agents fordizziness, tranquilizers, antipsychotics, muscle relaxants, drugs forParkinson's disease, respiratory agents, hormones, non-steroidalhormones, antihormones, vitamins, antitumor agents, miotics, herbmedicines, herb extracts, antimuscarinics, interferons, immunokines,cytokines, muscarinic cholinergic blocking agents, mydriatics, psychicenergizers, humoral agents, antispasmodics, antidepressant drugs,anti-diabetics, anorectic drugs, anti-allergenics, decongestants,expectorants, antipyretics, antimigrane, anti-malarials,anti-ulcerative, anti-estrogen, anti-hormone agents, anesthetic agent,or drugs having an action on the central nervous system. For example,for use in the treatment of cold/cough symptoms the active agents mayinclude one or more antihistamines, anti-tussives, expectorants and thelike, e.g., hyoscyamine, pseudoephedrine, chlorpheniramine,dextromethorphan, guaifenesin, and salts thereof or mixtures of saltsthereof. The chewable formulation may also include an analgesic or evena narcotic.

Examples of carriers for the actives of the present invention includeany degradable, partially degradable or non-degradable and generallybiocompatible polymer, e.g., polystirex, polypropylene, polyethylene,polacrilex, poly-lactic acid (PLA), poly-glycolic acid (PGA) and/orpoly-lactic poly-glycolic acid (PGLA) in the form or a matrix or even abead.

The present invention also includes those chewable formulations made bythe methods disclosed and claimed herein. For example, specific chewableformulation may include one or more active agents available forimmediate, modified and/or extended or controlled release for use intreating cold/cough/allergy symptoms. The one or more actives forcold/cough/allergy may include one or more of the following:anti-tussives, anti-histamines, expectorants and analgesics. Forexample, the actives may include hyoscyamine, pseudoephedrine,chlorpheniramine, dextromethorphan, guaifenesin, and salts thereof ormixtures of salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

Pharmaceutically active agents can be administered to the patient inmany forms with oral administration being the most popular as liquidsolutions, emulsions, suspensions or in solid form such as capsules ortablets. The oral administration is problematic for some individual(e.g., infants, children and older persons) that are unable to swallowwhole tablets and capsules. Therefore, it is desirable to administerdoses in a liquid form, a dissolvable form, a chewable form or in a formthat are absorbed through the oral mucosa.

Unlike tablets or capsules which are intended to be swallowed whole,forms that are absorbed through the oral mucosa must be formulated totake into account the taste of the active ingredient. Some therapeuticagents can cause strong negative sensory perceptions in the mouth due totheir delivery through the mucosa. Often the sensory perceptions are soobjectionable that a patient stops taking the medicine. In such cases,the use of conventional sweetener/flavor approach is not sufficient tomask or hide these negative perceptions. Conventional sweeteners and/orflavors are commonly used to prevent the taste from being apparentduring the time that the medicine is in the mouth.

The present invention may be used to taste-mask a wide range ofchemicals in a formulation depending on the predominant, secondary andtertiary taste. The selection of two, three or more masking agents maybe modified, without undue experimentation, by comparing the most commonpredominant, secondary and tertiary flavors or taste of the one or moreactives. Differences may also be determined between children and adults(e.g., changes in sweetness thresholds), males and females and inaccordance with the flavor of the final composition (e.g., cherry versusgrape).

The sense of taste caused by the excitation of taste receptors on thetongue. The tongue includes receptors for a large number of specificchemicals have been identified that contribute to the reception oftaste, e.g., chemicals as sodium, potassium, chloride, glutamate andadenosine. Despite this complexity, five types of tastes are commonlyrecognized: Salty, Sour, Sweet, Bitter and Umami. The umami taste isthat of monosodium glutamate and has recently been recognized as aunique taste, as it cannot be elicited by any combination of the otherfour taste types. Glutamate is present in a variety of protein-richfoods, and particularly abundant in aged cheese.

The perception of taste may also be influenced by thermal stimulation ofthe tongue. For example, in some people, warming the front of the tongueproduces a clear sweet sensation, while cooling leads to a salty or soursensation. Tastes are based on human sensations and some physiologistsbelieve that each animal probably has its own perception of taste.

As used herein, the terms “extended release,” “sustained release,” and“delayed release” are used to define a release profile to effectdelivery of an active over an extended period of time, defined herein asbeing between about 60 minutes and about 2, 4, 6, 8 or even 12 hours.Extended release may also be defined functionally as the release of over80 to 90 percent (%) of the active ingredient after about 60 minutes andabout 2, 4, 6 or even 8 hours. Extended release as used herein may alsobe defined as making the active ingredient available to the patient orsubject regardless of uptake, as some actives may never be absorbed bythe animal. Various extended release dosage forms may be designedreadily by one of skill in art as disclosed herein to achieve deliveryto both the small and large intestines, to only the small intestine, orto only the large intestine, depending upon the choice of coatingmaterials and/or coating thickness.

As used herein, the term “USP” is used to describe the United StatesPharmacopoeia a widely recognized organization that sets some of thestandards that pharmaceutical manufacturers must meet to sell theirdrugs and drug compounds in the United States. USP standards includeprocedures for the physical tests that must be performed on drugs anddrug compounds to ensure compliance with the specific requirements setforth within these standards.

As used herein, the term “pharmaceutically acceptable salts” is used todescribe those salts in which the anion (or cation) does not contributesignificantly to the toxicity or pharmacological activity of the salt,and, as such, they are the pharmacological equivalents of the bases ofthe compounds to which they refer. Examples of pharmaceuticallyacceptable acids that are useful for the purposes of salt formationinclude but are not limited to hydrochloric, hydrobromic, hydroiodic,citric, acetic, benzoic, mandelic, fumaric, succinic, phosphoric,nitric, maleic, mucic, isethionic, palmitic, tannic and others. Theactive salt combinations of the pharmacologic ingredients may be thefree acids, bases or as salts having anionic functional groups such asbitartrate, maleate, citrate, chloride, bromide, acetate and sulfate.The source of the functional groups may be natural or synthetic.

As used herein, the term “Controlled release” refers to the release ofan agent such as a drug from a composition or dosage form in which theagent is released according to a desired profile over an extended periodof time. Controlled release profiles include, for example, sustainedrelease, prolonged release, pulsatile release, and delayed releaseprofiles. In contrast to immediate release compositions, controlledrelease compositions allow delivery of an agent to a subject over anextended period of time according to a predetermined profile. Suchrelease rates can provide therapeutically effective levels of agent foran extended period of time and thereby provide a longer period ofpharmacologic or diagnostic response as compared to conventional rapidrelease dosage forms. Such longer periods of response provide for manyinherent benefits that are not achieved with the corresponding shortacting, immediate release preparations. For example, in the treatment ofchronic pain, controlled release formulations are often highly preferredover conventional short-acting formulations.

Controlled release pharmaceutical compositions and dosage forms aredesigned to improve the delivery profile of agents, such as drugs,medicaments, active agents, diagnostic agents, or any substance to beinternally administered to an animal, including humans. A controlledrelease composition is typically used to improve the effects ofadministered substances by optimizing the kinetics of delivery, therebyincreasing bioavailability, convenience, and patient compliance, as wellas minimizing side effects associated with inappropriate immediaterelease rates such as a high initial release rate and, if undesired,uneven blood or tissue levels.

The present invention provides a taste-masked pharmaceutical compositionincluding a drug-resin complex and a highly compressible, free-flowingpharmaceutical excipient. The resin is present in an amount effective toreduce the taste of the drug in the drug resin complex by patients thatis significant relative to an otherwise identical pharmaceuticalcomposition without the resin. The highly compressible, free-flowingpharmaceutical excipient the formulation to be compressed, whileallowing for rapid disintegration or breakdown by chewing in the mouth.The pharmaceutical composition includes a chewable tablet, a solid, aliquid, an orally disintegrable tablet, a gel, a tab, a powder, a gum, alozenge or a combination thereof. The disintegratable formulations maybe delivered to, and adapted for, oral, nasal, buccal, ocular, urethral,transmucosal, vaginal, topical or rectal delivery, although oraldelivery is used mostly. In addition, conventional excipients such ascolorants, anti-tack agents, fillers, plasticizers, pore forming agents,glossing agents, etc. can be added to the present invention.

The present invention provides a taste-masked chewable pseudoephedrineand chlorpheniramine pharmaceutical composition. The compositionincludes a pseudoephedrine-resin complex, a chlorpheniramine-resincomplex and one or more amorphous sugars. The composition also includesa compressible, free-flowing, pharmaceutical, taste-masking excipient,wherein the highly compressible, free-flowing pharmaceutical excipientcauses disintegration of the tablet and liberation of the drug-resincomplex in the mouth. In some instances the resin is polistirex,polyacrilex or a combination thereof, and more specificallypseudoephedrine polistirex and chlorpheniramine polyacrilex. Theamorphous sugar may be the commercially available Pharmaburst or othersugars known to the skilled artisan. However the skilled artisan willrecognize that other combinations of actives, resins and sugars may beused.

The present invention also includes a taste-masked soluble chewablepseudoephedrine and chlorpheniramine pharmaceutical composition. Thecomposition includes a pseudoephedrine-resin complex, achlorpheniramine-resin complex, one or more amorphous sugars and acompressible, free-flowing, pharmaceutical, taste-masking excipient. Thepseudoephedrine and the chlorpheniramine are slowly released when thecomposition is chewed. The composition becoming thixotropic when chewedbut not fully dissolving for at least 10 seconds, so as to dissolvethereafter in saliva during chewing.

The present invention includes a rapidly disintegrating, taste-maskedhyoscyamine pharmaceutical composition. The composition includes ahyoscyamine-resin complex, one or more amorphous sugars and acompressible, free-flowing, pharmaceutical, taste-masking excipient. Thehyoscyamine is slowly released as the tablet disintegrates. In someinstances the resin is polistirex, polyacrilex or a combination thereof,and more specifically hyoscyamine polistirex. The amorphous sugar may bethe commercially available Pharmaburst or other sugar known to theskilled artisan.

The present invention also includes a rapidly disintegrating,taste-masked hyoscyamine pharmaceutical composition. The compositionincludes a hyoscyamine-resin complex and one or more amorphous sugars.The hyoscyamine is slowly released when the composition is chewed, thecomposition becoming thixotropic when chewed but not fully dissolvingfor at least 10 seconds when chewed, and the composition slowlydissolves when the composition is chewed, so as to completely dissociatethereafter once swallowed. Alternatively, the active agent is slowlyreleased when the composition is chewed, the composition becomingthixotropic when chewed but not fully dissolving for at least 10 secondswhen chewed, and the composition slowly dissolves when the compositionis chewed; however the remaining material need not be swallowed and maybe discarded. The present invention may be formulated in a variety offorms including a chewable tablet, a solid, a liquid, a gel, a tab, acapsule, a disintegrating tablet, a powder, a lotion, a cream, a gum, alozenge or combination thereof.

Generally, the drug-resin complex includes an exchange resin, e.g.,cationic exchange resin. The resin may be divinylbenzene sulfonic acidcationic exchange resin, e.g., polistirex. In some embodiments thedrug-resin complex includes pseudoephedrine polistirex, chlorpheniraminepolistirex, hyoscyamine polistirex or a combination thereof.

The present invention includes a soluble chewable tablet including apharmaceutically active drug-resin complex. The pharmaceutically activeingredient is slowly released when the tablet is chewed. As the tabletis chewed it becomes thixotropic but not fully dissolving for at least30 seconds, rapidly disintegrating during chewing but preventing therelease of the ionic drug until after the complex is swallowed

The tablet may contain other conventional ingredients, including otherfillers, which include water-soluble compressible carbohydrates such asdextrose, sucrose, mannitol, sorbitol, maltitol, xylitol, lactose, andmixtures thereof; other conventional dry binders like polyvinylpyrrolidone and the like; sweeteners such as aspartame, acesulfamepotassium, sucralose, and saccharin; and lubricants, such as magnesiumstearate, stearic acid, talc, and waxes. The mixture may alsoincorporate pharmaceutically acceptable adjuvants, including, forexample, preservatives, flavors, antioxidants, surfactants, and coloringagents.

When in the form of a chewable tablet components include all thosesubstances which, alone or mixed with one another, behave like chewinggum for at least 5 seconds when chewed, but begin to disintegrate duringthis time and are then completely disintegrated and swallowed with thesaliva. The range of substances include, inter alia, but notexclusively, gum arabic, tragacanth, guar gum, xanthan gum, pectins; butalso dry syrups, such as, for example, dry glucose syrup and/or fructosesyrup; soluble cellulose derivatives, such as, for example, sodiumcarboxymethylcellulose. Dry glucose syrup likewise exhibits partlyrubber-like behavior on chewing.

The pharmaceutical composition of the present invention also includes anorally disintegrable composition having the amount of disintegrationagent, either effervescent or noneffervescent or the combination thereofprovided sufficient such that the composition provides a pleasantorganoleptic sensation in the mouth of the patient. In general, theamount of effervescence disintegration agent, noneffervescentdisintegration agent or both in accordance with the present inventionshould be sufficient to allow for the rapid and complete disintegrationof the composition when orally administered. Complete disintegration ofthe composition does not require dissolution or disintegration of themicroparticles or other discrete materials included.

The present invention may contain preservatives to prevent microbialcontamination. Examples of preservatives are the alkylparabens,particularly methylparaben, propylparaben and butylparaben. The amountof preservative generally used will vary depending upon the preservativeselected and may, for example, range from about 0.05% to about 15%weight/volume of the final composition. The preservative will be presentin an amount from about 0.01% to about 20% weight/volume of the finalcomposition.

In some instances the present invention may include a syrup componentincluding glucose syrup, maltodextrin solution, swollen gelatin, butalso other syrups, such as corn, sugar or invert sugar syrup. Glucosesyrup can be completely or partly replaced by other concentratedcarbohydrate, sugar alcohol, gelatin or similar solutions.

The present invention also includes a tablet formulation that has one ormore amorphous sugars. The skilled artisan will recognize that manyamorphous sugars may be used. Generally, amorphous sugar signifies asugar which is materially amorphous or which is capable of becomingamorphous. In the process of becoming amorphous there may be stateswhere a portion is not amorphous. Commercially, amorphous sugars such asMannogem EZ and Pharmaburst (both available from SPI Pharma, Lewes,Del.) may be used to provide fast delivery.

The skilled artisan will recognize that other amorphous sugars andcombinations of sugars may be used. Examples of amorphous sugars includeglucose, lactose, maltose, sorbitol, trehalose, lactitol, fructose,polyols and the like. Polyols may be used in the present invention andfunction as an additive, compacting agent, filler, and/or carriers interalia for active pharmaceutical ingredients. Polyols have sweeteningproperties which are comparable to those of sucrose and many polyolsshow a cooling effect, which is felt to be pleasant, during thedissolving process. Commonly used polyols include xylitol, mannitol,lactitol, isomalt and sorbitol.

Generally, polyols may be used in the present invention as they have asweet taste and can be used to provide a cooling effect in the mouth.Commonly-used polyols include xylitol, mannitol, sorbitol anderythritol. However, the skilled artisan will recognize that a varietyof polyols and combinations of polyols may be used. Xylitol is anodorless white crystalline powder that is comparably sweet to sucrose.The heat of solution of crystalline xylitol causes a strong coolingsensation in the mouth when the crystals dissolve. Crystalline xylitolcan also change the flavor profiled. Erythritol is an odorless whitecrystalline powder with a clean sweet taste that is similar to sucrose.The heat of solution of crystalline erythritol also causes a strongsensory cooling feeling in the mouth like xylitol. Sorbitol is a popularbulk sweetener found in numerous food products. In addition to providingsweetness, it is an excellent humectant and texturizing agent. Mannitolis a monosaccharide polyol. Both sorbitol and mannitol are generallystable and chemically unreactive.

In addition cellulose esters such as cellulose acetate and celluloseacetate butyrate, and cellulose triacetate may be used as taste maskingagents since they do not dissolve in the mouth and are tough enough toremain effectively intact during processing and normal chewing in themouth.

Adsorption of the active ingredient onto the ion exchange resinparticles to form the active agent-resin complex is a well-knowntechnique as shown in U.S. Pat. No. 2,990,332 (relevant portionsincorporated herein by reference) and demonstrated in the exampleshereinbelow. In general, the active ingredient is mixed with an aqueoussuspension of the resin and the complex is then dried. Adsorption of theactive ingredient onto the resin is detected by a change in the pH ofthe reaction medium.

In accordance with the present invention the active ingredient can beany pharmaceutically active material and can also include vitamins,minerals, nutritional supplements and the like. These can include,without limitation systematically distributable pharmaceutically activematerials, vitamins, minerals, dietary supplements, as well asnon-systematically distributable pharmaceutically active materials.Drugs or pharmaceutically active materials may include, withoutlimitation, antacids, analgesics, anti-inflammatories, antipyreticsantibiotics, antimicrobials, laxatives, anorexics, antihistamines,antiasthmatics, antidiuretics, antiflatuents, antimigraine agents,antispasmodics, sedatives, antihyperactives, antihypertensives,tranquilizers, decongestants, beta blockers and combinations thereof.

In addition, nanoparticulate and microparticulate active agents may beused in the present invention and may include proteins, peptides,nucleotides, anti-obesity drugs, nutraceuticals, corticosteroids,elastase inhibitors, anti-fungals, oncology therapies, anti-emetics,analgesics, cardiovascular agents, anti-inflammatory agents,anthelmintics, anti-arrhythmic agents, antibiotics, anticoagulants,antidepressants, antidiabetic agents, antiepileptics, antihistamines,antihypertensive agents, antimuscarinic agents, antimycobacterialagents, antineoplastic agents, immunosuppressants, antithyroid agents,antiviral agents, anxiolytics, sedatives, astringents, beta-adrenoceptorblocking agents, blood products and substitutes, cardiac inotropicagents, contrast media, corticosteroids, cough suppressants, diagnosticagents, diagnostic imaging agents, diuretics, dopaminergics,haemostatics, immunological agents, lipid regulating agents, musclerelaxants, parasympathomimetics, parathyroid calcitonin andbiphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones,anti-allergic agents, stimulants and anoretics, sympathomimetics,thyroid agents, vasodilators, and xanthines.

Substrates include a powder that constitutes a finely divided (e.g.,milled, micronized, nanosized, precipitated) form of an activeingredient or additive molecular aggregates or a compound aggregate ofmultiple components or a physical mixture of aggregates of an activeingredient and/or additives. Such substrates may be formed of variousmaterials known in the art, such as, for example sugars (e.g., lactose,sucrose or dextrose), polysaccharides (e.g., maltodextrin or dextrates),starches, cellulosics (e.g., microcrystalline cellulose ormicrocrystalline cellulose/sodium carboxymethyl cellulose), inorganics(e.g., dicalcium phosphate, hydroxyapitite, tricalcium phosphate, talc,or titania) and polyols (e.g., mannitol, xylitol, sorbitol orcyclodextrin).

Flavoring agents that may be used in the present invention include, andare not limited to, natural flavors, natural fruit flavors, artificialflavors, artificial fruit flavors, flavor enhancers or mixtures thereof.Natural flavors, artificial flavors or mixtures thereof include, and arenot limited to, mint (e.g., peppermint or spearmint), lemon, lime,orange, strawberry, menthol, cinnamon, vanilla, artificial vanilla,chocolate, artificial chocolate or bubblegum. Natural fruit flavors,artificial fruit flavors or mixtures thereof include, and are notlimited to, cherry, grape, orange, strawberry or lemon. Flavor enhancersinclude, and are not limited to, citric acid. Although flavoring agentsare generally provided as a minor component of the taste maskingcomposition in amounts effective to provide a palatable flavor to theliquid pharmaceutical composition, the addition of at least oneflavoring agent is preferred; and, more preferably, up to two flavoringagents may be employed. A flavoring agent used in the taste maskingcomposition has a range of from about 0.01 to about 0.15 grams per 100mL. The flavorings are generally utilized in amounts that will varydepending upon the individual flavor, and may, for example, range inamounts of about 0.01% to about 10% by weight/volume of the finalcomposition.

Examples of sweeteners include sweetening agents, artificial sweetenersand dipeptide based sweeteners, e.g., monosaccharides, disaccharides andpolysaccharides such as xylose, ribose, glucose, mannose, galactose,fructose, dextrose, sucrose, sugar, maltose, partially hydrolyzedstarch, or corn syrup solids and sugar alcohols such as sorbitol,xylitol, mannitol, saccharin salts, i.e., sodium, or calcium saccharinsalts, cyclamate salts, acesulfam-K, ammonium glycyrrhizinate,dipotassium glycyrrhizinate and the free acid form of saccharinL-aspartylphenylalanine methyl ester and mixtures thereof.

Generally, the sweetener will be present in an amount corresponding toabout 1 to 60% weight/volume of the total composition, the amountdepending in part upon whether other sweetener ingredients are presentand the level of sweetness desired. Typically sugar is used it ispresent from about 10% to about 50% w/v of the composition. It will beappreciated that combinations of sweeteners can be used. The sweeteningagents, when used, may also be used alone or in combination with eachother. When an artificial sweetness enhancer is used it may be presentin an amount from about 0.05% to about 15% weight/volume of the finalcomposition.

The colorants useful in the present invention include pigments such astitanium dioxide, that may be incorporated in amounts of up to about 10%by weight/volume. The colorants may include other dyes suitable forfood, drug and cosmetic applications, and known as F.D. & C. dyes andthe like. The materials acceptable for the foregoing spectrum of use maybe water-soluble. Illustrative examples include indigoid dye, known asF.D. & C. Blue No. 2, which is the disodium salt of5,5′-indigotindisulfonic acid. Similarly, the dye known as F.D. & C.Green No. 1, includes a triphenylmethane dye and is the monosodium saltof4-[4-Nethyl-p-sulfobenzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulfoniumbenzyl)-2,5-cyclohexadienimine].

Examples of organic acids for use with the formulations include, e.g.,citric acid, tartaric acid, succinic acid, malic acid, fumaric acid,hydroxybenzoic acid and the like. The hydroxybenzoic acids includeparaben esters of p-hydroxybenzoic acid (e.g., methyl paraben, ethylparaben, propyl paraben, butyl paraben and benzyl paraben). Salts ofdrugs where the anion of the salt is acidic, such as acetate,hydrochloride, hydrobromide, sulfate, succinate, citrate, and the like,may be used to produce immediate disintegration and dissolution of theporous particle. Some variation in dosage will necessarily occurdepending on the condition of the subject being treated. The personresponsible for administration will, in any event, determine theappropriate dose for the individual subject. Moreover, for humanadministration, preparations should meet sterility, pyrogenicity,general safety and purity standards as required by FDA Office ofBiologics standards. The interaction of an acidic component with, e.g.,a porous particle of, for example, calcium hydrogen phosphate, in thepresence of water from gastric fluids accelerates dissolution of theparticle at a greater rate than gastric fluid alone, producing a morerapid and complete release of the liquid, active agent formulation intothe environment of use. Alternatively, alkaline components or salts ofdrugs may be used if the cation of the salt is alkaline such as cholinemay be incorporated into the liquid, active agent formulation to promoterapid and complete dissolution of a porous particle which is soluble orswells at elevated pH. Such a particle may be formed, e.g., ofpoly(methacrylic acid-methyl methacrylate) 1:2 available commercially asEudragit S100 (Rohm America, Sommerset, N.J.).

Other additives conventionally used in pharmaceutical compositions maybe included, which are well known in the art. Such additives include,e.g., anti-adherents (e.g, anti-sticking agents, glidants, flowpromoters, lubricants) such as talc, magnesium stearate, fumed silica),micronized silica, polyethylene glycols, surfactants, waxes, stearicacid, stearic acid salts, stearic acid derivatives, starch, hydrogenatedvegetable oils, sodium benzoate, sodium acetate, leucine, PEG-4000 andmagnesium lauryl sulfate. The present invention includes purified,hydrated, magnesium silicate (i.e., talc) which is widely used in oralsolid dosage forms as a lubricant and diluent.

Pharmaceutical compositions according to the invention may also includeone or more binding agents, filling agents, lubricating agents,suspending agents, sweeteners, flavoring agents, preservatives, buffers,wetting agents, disintegrants, effervescent agents, and otherexcipients. Such components are known to the skilled artisan.

Examples of filling agents include lactose monohydrate, lactoseanhydrous, and various starches. Examples of binding agents includevarious celluloses and cross-linked polyvinylpyrrolidone,microcrystalline cellulose, microcrystalline cellulose, and silicizedmicrocrystalline cellulose. Generally, suitable lubricants, includingagents that act on the flowability of the powder to be compressed, arecolloidal silicon dioxide, talc, stearic acid, magnesium stearate,calcium stearate, and silica gel.

Examples of preservatives include sorbates, and parabens, e.g.,potassium sorbate, methylparaben, propylparaben, benzoic acid and itssalts, other esters of parahydroxybenzoic acid such as butylparaben,alcohols such as ethyl or benzyl alcohol, phenolic compounds such asphenol, or quarternary compounds such as benzalkonium chloride. Inaddition suitable diluents include pharmaceutically acceptable inertfillers, such as microcrystalline cellulose, lactose, dibasic calciumphosphate, saccharides, and/or mixtures of any of the foregoing.

The present invention includes disintegrants which include lightlycrosslinked polyvinyl pyrrolidone, corn starch, potato starch, maizestarch, and modified starches, croscarmellose sodium, cross-povidone,sodium starch glycolate, and mixtures thereof. Some embodiments of thepresent invention are in the form of effervescent compositions. Examplesof effervescent agents include an organic acid and a carbonate orbicarbonate. Suitable organic acids include, for example, citric,tartaric, malic, fumaric, adipic, succinic, and alginic acids andanhydrides and acid salts. Suitable carbonates and bicarbonates include,for example, sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, magnesium carbonate, sodium glycine carbonate,L-lysine carbonate, and arginine carbonate. Alternatively, only the acidcomponent of the effervescent couple may be present invention.

For certain actives it may be useful to provide buffering agents, wherethe acid is a pharmaceutically acceptable acid, such as hydrochloricacid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid,boric acid, phosphoric acid, acetic acid, acrylic acid, adipic acid,alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoicacid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids,formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid,isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalicacid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonicacid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaricacid, thioglycolic acid, toluenesulfonic acid and uric acid, and wherethe base is a pharmaceutically acceptable base, such as an amino acid,an amino acid ester, ammonium hydroxide, potassium hydroxide, sodiumhydroxide, sodium hydrogen carbonate, aluminum hydroxide, calciumcarbonate, magnesium hydroxide, magnesium aluminum silicate, syntheticaluminum silicate, synthetic hydrotalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, or a salt of a pharmaceuticallyacceptable cation and acetic acid, acrylic acid, adipic acid, alginicacid, alkanesulfonic acid, an amino acid, ascorbic acid, benzoic acid,boric acid, butyric acid, carbonic acid, citric acid, a fatty acid,formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid,isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalicacid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonicacid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaricacid, thioglycolic acid, toluenesulfonic acid, and uric acid. The bufferinclude acids and their base salts for example, citric acid (e.g.,citric acid anhydrous), tartaric acid, malic acid, phosphoric acid andthe like and their respective salts.

The present invention may also include one or more binders. The choiceof binder for a given application may also be determined readily bythose skilled in the art. Generally, the binder must be capable ofwetting the surfaces of the particle being pelletized or granulated. Ingeneral, binders must have sufficient wet strength to allow agglomeratesto be handled and sufficient dry strength to make them suitable fortheir intended purposes. Each process, however, makes use of a differentsystem of forces and may require a different agglomerate strength. Thefinal selection of the binder is made generally based on the type ofequipment used. Factors that affect the equipment and binder choicesinclude: the size and size distribution of pellets, bulk density,strength and flow properties. Other factors that affect the performanceof the pellets, which may be adjusted by one skilled in the art by theinclusion of additives, choice of equipment and processing conditions.

The present invention may also include one or more coolants that willcontribute a cooling sensation to products in which it is found withoutthe unwanted harshness or flavor characteristics. Generally, coolantsare compounds that provide a physiological cooling effect on the skin oron the mucous membranes of the body, particularly the mucous membranesof the nose and bronchial tract. For example, Menthol is well known forits physiological cooling effect on the skin and mucous membranes of themouth. The “cooling” effect of menthol is a physiological effect due tothe direct action of menthol on the nerve endings of the human bodyresponsible for the detection of hot or cold and is not due to latentheat of evaporation. It is believed that the menthol acts as a directstimulus on the cold receptors at the nerve endings, which in turnstimulate the central nervous system. In addition, menthol is a majorconstituent of oil of peppermint and may function as a flavoring aswell. Since many of the physiological cooling agents do not have theirown perceptible flavor they can be combined with other types of flavorsto offer new and unique advantages.

Physiological cooling agents that may be used in the present inventioninclude menthol, menthone glycerol ketal, menthyl lactate,N-ethyl-p-menthane-3-carboxamide, 3-1-menthoxypropane-1,2,diol,3-substituted-P-menthanes, N-substituted-P-menthane-3-carboxamides and3-1-menthoxypropane-1,2-diol, 3-1-menthoxypropane-1,2-diol, a ketalcombined with another coolant (e.g., menthol or carboxamides),physiological cooling agents and reduced menthol, menthone ketals,menthone glycerol ketals, cyclodextrin complex with physiologicalcooling agents, ketoesters of menthol, sulphoxides and sulphones,acyclic carboxamides, menthyl lactate, cyclohexanamides, carbonic acidshaving free polar groups, acyclic secondary and tertiary alkanols,menthyl succinate and carboxamides, alpha-oxy(oxo)mercaptan alkanes,acyclic sulphonamides and sulphinamides, substitutedp-menthane-3-carboxamides, substituted cyclohexanamides, alkylsubstituted alicyclic carboxylic acids, alkyl substituted alicyclicesters, alkyl substituted alicyclic amides, 3-substituted p-menthanes,p-menthane-3-carboxylates, N-acetylglycine menthyl ester,L-menthyl-3-hydroxybutyrate, 2-isopropenyl-5-methylcyclohexanol,bicyclic acids, esters, amides and substituted menthanols,trialkyl-substituted cyclohexane carboxamides, cyclic and acyclicamides, ureas and sulphonamides, p-menthane carboxamide physiologicalcooling agent with menthol, 3-I-menthoxypropane-1,2-diol, N-substitutedp-menthane carboxamides and menthol, cyclohexanol derivatives,substituted p-menthanes, substituted p-menthane-carboxamides (e.g.,N-ethyl-p-menthane-3-carboxamide), acyclic darboxamides, substitutedcyclohexanamides, substituted cyclohexane carboxamides, substitutedureas and sulphonamides, and substituted menthanols, hydroxymethyl andhydroxyethyl derivatives of p-menthane, menthyl succinate,2-mercapto-cyclo-decanone, 2-isopropanyl-5-methylcyclohexanol,hydroxycarboxylic acids with 2-6 carbon atoms, menthone glycerol ketals,3-I-menthoxypropane-1,2-diol, menthyl lactate, substituted p-menthanecarboxamides (PMC), N-ethyl-p-menthane-3-carboxamide, acycliccarboxamides (AC), N-2,3-trimethyl-2-isopropyl butanamide,N-ethyl-2,3-dimethyl-2-isopropyl butanamide, N,2,3-trimethyl-2-isopropyl butanamide, menthone glycerol ketal (MGK),menthyl lactate (ML), menthyl succinate (MS),3-I-menthoxypropane-1,2-diol (TCA). Physiological cooling agents maygenerally be of the chemical classification of ketone, hemi ketal,ketal, acetal, or hemiacetal.

Stearic acid is commonly used in the pharmaceutical industry primarilyas a lubricant for tablets and capsules. It is typically used in aconcentration of 1% to 10% when used as a tablet lubricant. Stearic acidis described as a mixture of stearic acid and palmitic acid. The contentof stearic acid is not less than about 10% and the sum of the two acidsis not less than about 90.0%. Stearic acid is used as an emulsifyingagent; solubilizing agent; tablet and capsule lubricant. The purpose inthis formulation is that of a lubricant of the gauifenesin so that anadequate plug can be produced and delivered through the dosing diskwithout excessive wear.

Suitable excipients are those used commonly to facilitate the processesinvolving the preparation of the solid carrier, the encapsulationcoating, or the pharmaceutical dosage form. These processes includeagglomeration, air suspension chilling, air suspension drying, balling,coacervation, comminution, compression, pelletization,cryopelletization, extrusion, granulation, homogenization, inclusioncomplexation, lyophilization, nanoencapsulation, melting, mixing,molding, pan coating, solvent dehydration, sonication, spheronization,spray chilling, spray congealing, spray drying, or other processes knownin the art. The excipients may also be pre-coated or encapsulated, asare well known in the art.

The excipient in the form of a hydrate may be selected from organiccompounds such as dextrose monohydrate, maltodextrin, lactosemonohydrate, dextrin, and citric acid monohydrate, as well as inorganiccompounds including dibasic calcium phosphate dihydrate, dibasic sodiumphosphate dihydrate, dibasic sodium phosphate heptahydrate, dibasicsodium phosphate dodecahydrate, monobasic sodium phosphate monohydrate,and monobasic sodium phosphate dihydrate. Preferably, the excipient inthe form of a hydrate is an organic compound, more preferably dextrosemonohydrate.

The present invention may include calcium stearate and/or magnesiumstearate which are primarily used in pharmaceutical formulations as alubricant in tablet and capsule manufacture. Calcium stearate has goodanti-adherent and lubricant properties. Maltodextrin is used in tabletformulations as a binder and diluent in both direct compression and wetgranulation process. Maltodextrin appears to have no adverse effects onthe rate of tablet dissolution. As a binder it is typically used inconcentrations of 1% to 25%.

The pharmaceutical compositions of the present invention may includeoptionally one or more solubilizers, i.e., additives to increase thesolubility of the pharmaceutical active ingredient or other compositioncomponents in the solid carrier. It has been recognized by the presentinventors that guaifenesin, in fact, acts as a solubilizer forphenylephrine, and is used as such in the examples provided herein.Other solubilizers are known in the art. Mixtures of solubilizers arealso within the scope of the invention and are readily available fromstandard commercial sources.

The amount of solubilizer that may be included in compositions of thepresent invention is not particularly limited. Of course, when suchcompositions are administered to a patient, the amount of a givensolubilizer is limited to a bioacceptable amount, which is readilydetermined by one of skill in the art. In some circumstances, it may beadvantageous to include amounts of solubilizers far in excess ofbioacceptable amounts, for example, to maximize the concentration ofactive ingredient, with excess solubilizer removed prior to providingthe composition to a patient using conventional techniques, such asdistillation or evaporation.

In some formulations additives may also include chelating agents (e.g.,EDTA and EDTA salts); colorants or opaquants (e.g., titanium dioxide,food dyes, lakes, natural vegetable colorants, iron oxides, silicates,sulfates, magnesium hydroxide and aluminum hydroxide); coolants (e.g.,trichloroethane, trichloroethylene, dichloromethane,fluorotrichloromethane); cryoprotectants (e.g., trehelose, phosphates,citric acid, tartaric acid, gelatin, dextran and mannitol); and diluentsor fillers (e.g., lactose, mannitol, talc, magnesium stearate, sodiumchloride, potassium chloride, citric acid, spray-dried lactose,hydrolyzed starches, directly compressible starch, microcrystallinecellulose, cellulosics, sorbitol, sucrose, sucrose-based materials,calcium sulfate, dibasic calcium phosphate and dextrose). Yet otheradditives may include disintegrants or super disintegrants; hydrogenbonding agents, such as magnesium oxide; flavorants or desensitizers.

The present invention may also include one or more surface stabilizerselected from the group consisting of cetyl pyridinium chloride,gelatin, casein, phosphatides, dextran, glycerol, gum acacia,cholesterol, tragacanth, stearic acid, stearic acid esters and salts,calcium stearate, glycerol monostearate, cetostearyl alcohol,cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkylethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitanfatty acid esters, polyethylene glycols, dodecyl trimethyl ammoniumbromide, polyoxyethylene stearates, colloidal silicon dioxide,phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium,hydroxypropyl celluloses, hydroxypropyl methylcellulose,carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,hydroxypropylmethyl-cellulose phthalate, noncrystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol,polyvinylpyrrolidone, 4-(1,1,3,3-tetramethylbutyl)-phenol polymer withethylene oxide and formaldehyde, poloxamers, poloxamines, a chargedphospholipid, dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate,dialkylesters of sodium sulfosuccinic acid, sodium lauryl sulfate, alkylaryl polyether sulfonates, mixtures of sucrose stearate and sucrosedistearate, triblock copolymers of the structure:-(-PEO)-(—PBO—)-(-PEO-)-, p-isononylphenoxypoly-(glycidol),decanoyl-N-methylglucamide; n-decyl β-D-glucopyranoside, n-decylβ-D-maltopyranoside, n-dodecyl β-D-glucopyranoside, n-dodecylβ-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl β-D-thioglucoside, n-hexylβ-D-glucopyranoside, nonanoyl-N-methylglucamide, n-noylβ-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl β-D-thioglucopyranoside, lysozyme, aPEG derivatized phospholipid, PEG derivatized cholesterol, a PEGderivatized cholesterol derivative, PEG derivatized vitamin A, PEGderivatized vitamin E, and random copolymers of vinyl acetate and vinylpyrrolidone, biopolymers, polysaccharides, cellulosics, cationic lipids,benzalkonium chloride, sulfonium compounds, phosphonium compounds,quarternary ammonium compounds, benzyl-di(2-chloroethyl)ethylammoniumbromide, coconut trimethyl ammonium chloride, coconut trimethyl ammoniumbromide, coconut methyl dihydroxyethyl ammonium chloride, coconut methyldihydroxyethyl ammonium bromide, decyl triethyl ammonium chloride, decyldimethyl hydroxyethyl ammonium chloride, decyl dimethyl hydroxyethylammonium chloride bromide, C₁₂₋₁₅ dimethyl hydroxyethyl ammoniumchloride, C₁₂₋₁₅ dimethyl hydroxyethyl ammonium chloride bromide,coconut dimethyl hydroxyethyl ammonium chloride, coconut dimethylhydroxyethyl ammonium bromide, myristyl trimethyl ammonium methylsulphate, lauryl dimethyl benzyl ammonium chloride, lauryl dimethylbenzyl ammonium bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride,lauryl dimethyl (ethenoxy)4 ammonium bromide, N-alkyl(C₁₂₋₁₈)dimethylbenzyl ammonium chloride, N-alkyl(C₁₄₋₁₈)dimethyl-benzyl ammonium chloride, N-tetradecylidmethylbenzylammonium chloride monohydrate, dimethyl didecyl ammonium chloride,N-alkyl and (C₁₂₋₁₄) dimethyl 1-napthylmethyl ammonium chloride,trimethylammonium halide, alkyl-trimethylammonium salts,dialkyl-dimethylammonium salts, lauryl trimethyl ammonium chloride,ethoxylated alkyamidoalkyldialkylammonium salt, an ethoxylated trialkylammonium salt, dialkylbenzene dialkylammonium chloride,N-diclecyldimethyl ammonium chloride, N-tetradecyldimethylbenzylammonium, chloride monohydrate, N-alkyl(C₁₂₋₁₄) dimethyl1-naphthylmethyl ammonium chloride, dodecyldimethylbenzyl ammoniumchloride, dialkyl benzenealkyl ammonium chloride, lauryl trimethylammonium chloride, alkylbenzyl methyl ammonium chloride, alkyl benzyldimethyl ammonium bromide, C₁₂ trimethyl ammonium bromides, C₁₅trimethyl ammonium bromides, C₁₇ trimethyl ammonium bromides,dodecylbenzyl triethyl ammonium chloride, poly-diallyldimethylammoniumchloride, dimethyl ammonium chlorides, alkyldimethylammoniumhalogenides, tricetyl methyl ammonium chloride, decyltrimethylammoniumbromide, dodecyltriethylammonium bromide, tetradecyltrimethylammoniumbromide, methyl trioctylammonium chloride, tetrabutylammonium bromide,benzyl trimethylammonium bromide, choline esters, benzalkonium chloride,stearalkonium chloride compounds, cetyl pyridinium bromide, cetylpyridinium chloride, halide salts of quaternizedpolyoxyethylalkylamines, alkyl pyridinium salts; amines, amine salts,amine oxides, imide azolinium salts, protonated quaternary acrylamides,methylated quaternary polymers, cationic guar, polymethylmethacrylatetrimethylammonium bromide, polyvinylpyrrolidone-2-dimetbylaminoethylmethacrylate dimethyl sulfate, hexadecyltrimethyl ammonium bromide,poly(2-methacryloxyethyltrimethylammonium bromide),poly(N-vinylpyrrolidone/2-dimethylaminoethyl methacrylate)dimethylsulphate quarternary andpoly(2-methylacryloxyamidopropyltrimethylammonium chloride).

Pelletizers are generally classified based on the angle of their axis asa horizontal drum or an inclined dish pelletizer. Rotary fluidizedgranulators may also be used for pelletization. A standard fluidizeddrier bowl may be replaced with a rotating plate as an air distributor.For granulation, a binder liquid is sprayed from via one or two binarynozzles located axially to the rotational movement of the powder bed.The granulation results in rounding of the granules to approximatelyspherical pellets. Such balling or agitation techniques are generallyinfluenced by operating conditions, e.g., the bridging/binding liquidrequirements, the residence time of the material in the pelletizer, thespeed and angle of inclination of the pelletizer, the amount of materialfed to the pelletizer and the choice and levels of binder, etc. Thoseskilled in the art may adjust readily such factors to produce asatisfactory product.

A pelletization process typically involves preparing a molten solutionof the composition of the solid carrier or a dispersion of thecomposition of the solid carrier solubilized or suspended in an aqueousmedium, an organic solvent, a supercritical fluid, or a mixture thereof.Such solution or dispersion is then passed through a certain opening toachieve the desired shape, size, and other properties. Similarly,appropriate drying processes may be used to control the level of theresidual dispersing medium, if necessary. The processes described above,the combination of the processes, or the modification of the processesare well know in the art.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing, in a suitable machine, the therapeutic ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface therapeutic ordispersing agent. Molded tablets may be made by molding, in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may be optionally coated or scored and maybe formulated so as to provide a slow or controlled release of thetherapeutic ingredient therein.

The tablet may be made in any manner, and a variety of tableting methodsare known in the art. Conventional methods for tablet production includedirect compression (“dry blending”), dry granulation followed bycompression, and wet granulation followed by drying and compression.Other methods include the use of compacting roller technology, e.g., achilsonator (e.g., a dry granulation/roll compactor roller presssystem), drop roller, molding, casting, or extrusion technologies. Allof these methods are well known in the art. The tablets are formed bythe direct compression method, which involves directly compacting ablend of the active ingredient, the excipient in the form of a hydrate,the water-swellable excipient, and any other appropriate optionalingredients. After blending, a pre-determined volume of particles isfilled into a die cavity of a rotary tablet press, which continuouslyrotates as part of a “die table” from the filling position to acompaction position. The particles are compacted between an upper punchand a lower punch to an ejection position, at which the resulting tabletis pushed from the die cavity by the lower punch and guided to anejection chute by a stationary “take-off” bar.

Two examples of the present invention include a chewable tablet with thefollowing formulations:

Example I

First active ingredient polistirex 100.00 mg Second active ingredientpolistirex 15.00 mg Pharamaburst 170.00 mg Sorbitol 100.00 mg Sweetener25.00 mg Xylisorb 30.00 mg Citric acid 10.00 mg Flavor 7.50 mg Dye 2.50mg Talc 40.00 mg Steric acid 10.00 mg

Example II

Pseudoephedrine polistrex 99.70 mg Chlorpheniramine polyacrilex 14.70 mgPharamaburst 170.00 mg Sorbitol 100.00 mg Aspertame 25.00 mg Xylisorb30.00 mg Citric acid 10.00 mg Grape Flavor 7.50 mg Purple Lake Blend2.50 mg Talc 40.00 mg Steric acid 10.00 mg

Below is a list of actual assay results for one example of the presentinvention with the composition listed as formula II above. Thedissolution profile for the release of pseudoephedrine andchlorpheniramine are shown in Table 1, below.

TABLE 1 30 min(%) 1 Hr (%) 3 Hr (%) 8 Hr (%) Chlorpheniramine 35.1 42.751.6 60.8 Pseudoephedrine 27.6 37.8 59.4 82.0

Based on assay and dissolution profile 35.1% of the chlorpheniramine isreleased within 30 minutes. The release of chlorpheniramine at 1 hour isabout 42.7%. The release profile after 3 hours and 8 hours demonstrate arelease of 51.6% and 60.8% respectively. The dissolution profile alsoshows that 26.7% he pseudoephedrine is released within 30 minutes. Therelease of pseudoephedrine at 1 hour is about 37.8%. The release profileafter 3 hours and 8 hours demonstrate a release of 59.4% and 82.0%respectively.

Example III

Pseudoephedrine polistrex 102.92 mg Chlorpheniramine polyacrilex 15.11mg Pharamaburst 170.00 mg Sorbitol 86.97 mg Aspertame 25.00 mg Xylisorb30.00 mg Citric acid 10.00 mg Grape Flavor 7.50 mg Purple Lake Blend2.50 mg Talc 40.00 mg Steric acid 10.00 mg

Below is a list of assay results for one example of the presentinvention with the composition listed as formula II above. Thedissolution profile for the release of pseudoephedrine andchlorpheniramine are shown in Table 2, below.

TABLE 2 30 min (%) 1 Hr (%) 3 Hr (%) 8 Hr (%) Chlorpheniramine 36.4 42.151.0 60.7 Pseudoephedrine 27.0 36.3 53.0 78.4

Based on assay and dissolution profile 36.4% of the chlorpheniramine isreleased within 30 minutes. The release of chlorpheniramine at 1 hour isabout 42.1%. The release profile after 3 hours and 8 hours demonstrate arelease of 51.0% and 60.7% respectively. The dissolution profile alsoshows that 27.0% of the pseudoephedrine is released within 30 minutes.The release of pseudoephedrine at 1 hour is about 36.3%. The releaseprofile after 3 hours and 8 hours demonstrate a release of 53.0% and78.4% respectively.

Below is a list of actual assay results for one example of the presentinvention with the composition listed as formula II above. Thedissolution profile for the release of pseudoephedrine andchlorpheniramine are shown in Table 3, below.

TABLE 3 30 min (%) 1 Hr (%) 3 Hr (%) 8 Hr (%) Chlorpheniramine 40.1 45.153.3 62.1 Pseudoephedrine 29.2 39.7 61.2 85.2

Based on assay and dissolution profile 29.2% of the pseudoephedrine isreleased within 30 minutes. The release of pseudoephedrine at 1 hour isabout 39.7%. The release profile after 3 hours and 8 hours demonstrate arelease of 61.2% and 85.2% respectively. The dissolution profile alsoshows that 40.1% of the chlorpheniramine is released within 30 minutes.The release of chlorpheniramine at 1 hour is about 45.1%. The releaseprofile after 3 hours and 8 hours demonstrate a release of 53.3% and62.1% respectively.

In addition the composition may be in the form of a capsule. Below is alist of actual assay results for one example of the present inventionwhen in the form of a capsule. The dissolution profile for the releaseof pseudoephedrine and chlorpheniramine are shown in Table 4, below.

TABLE 4 Capsules 90 min (%) 3 Hr (%) 6 Hr (%) 12 Hr (%) Pseudoephedrine34.8 54.1 75.4 91.7 Chlorpheniramine 21.9 35.4 55.2 78.6

Based on assay and dissolution profile of the capsule 34.8% of thepseudoephedrine is released within 90 minutes. The release ofpseudoephedrine at 3 hour is about 54.1%. The release profile after 6hours and 12 hours demonstrate a release of 75.4% and 91.7%respectively. The dissolution profile also shows that 21.9% of thechlorpheniramine is released within 90 minutes. The release ofchlorpheniramine at 3 hour is about 35.4%. The release profile after 6hours and 12 hours demonstrate a release of 55.2% and 78.6%respectively.

Generally, sorbitol is highly compressible and binds other tabletingredients and may be used in pharmaceutical tablets, powders, andsachets. It may be used in direct compression tableting have particlesize distributions that make them free-flowing. The particle size iscontrolled to optimize the flow characteristics of the granulations inmodern tablet presses. Sorbitol increases the strength and integrity ofa pharmaceutical tablet. The skill artisan will recognize that othersubstances may be used in place of sorbitol or in addition to sorbitol.

Example IV

Pseudoephedrine polistrex 102.92 mg Chlorpheniramine polyacrilex 15.11mg Pharamaburst 170.00 mg Sorbitol 86.97 mg Aspertame 25.00 mg Xylisorb30.00 mg Citric acid 10.00 mg Grape Flavor 7.50 mg Purple Lake Blend2.50 mg Talc 40.00 mg Steric acid 10.00 mg

Example V

Active ingredient polistirex 0.33 mg Amorphous sugar 150.00 mgExcipient/binder 10.00 mg Sweetener 5.00 mg Coolant 2.67 mg Flavor 6.00mg Dye 0.50 mg Talc 30.00 mg Steric acid 5.00 mg

Example VI

Hyoscyamine polistirex 0.33 mg Pharmaburst 150.00 mg Povidone 10.00 mgAspertame 5.00 mg Coolant 2.67 mg Peppermint Flavor 6.00 mg Lake BlendLt Green 0.50 mg Talc 30.00 mg Steric acid 5.00 mg

Example VII

Hyoscyamine polistirex 0.33 mg Mannogem ™ EZ 150.00 mg Povidone 10.00 mgAspertame 5.00 mg Coolant 2.67 mg Peppermint Flavor 6.00 mg Lake BlendLt Green 0.50 mg Talc 30.00 mg Steric acid 5.00 mg

When formulated with microparticles or nanoparticles, the one or moreactives the release profile can easily be adapted by adding, e.g., ahard or soft gelatin coating, a starch coating, a resin or polymercoating and/or a cellulosic coating. Although not limited tomicroparticles or nanoparticles such dosage forms may be further coatedwith, for example, a seal coating, an enteric coating, an extendedrelease coating, or a targeted delayed release coating. The term“enteric coating” as used herein relates to a mixture ofpharmaceutically acceptable excipients that is applied to, combinedwith, mixed with or otherwise added to the carrier or composition. Thecoating may be applied to an active that is compressed, molded orextruded and may also include: gelatin, and/or pellets, beads, granulesor particles of the carrier or composition. The coating may be appliedthrough an aqueous dispersion or after dissolving in appropriatesolvent. The carrier may or may not be fully or partially biodegradable.

Carriers for use with the present invention include permeable andsemipermeable matrices or polymers that control the releasecharacteristics of the formulation. Such polymers include, for example,cellulose acylates, acetates, and other semi-permeable polymers as wellas the selectively permeable polymers formed by the coprecipitation of apolycation and a polyanioni. The carrier of the compositions of thepresent invention may be a powder or a multiparticulate, such as agranule, a pellet, a bead, a spherule, a beadlet, a microcapsule, amillisphere, a nanocapsule, a nanosphere, a microsphere, a platelet, aminitablet, a tablet or a capsule. A carrier may be a finely divided(e.g., milled, micronized, nanosized, precipitated) form of a matrix onwhich the active ingredient is disposed. Such matrix may be formed ofvarious materials known in the art, such as, for example: sugars, suchas lactose, sucrose or dextrose; polysaccharides, such as maltodextrinor dextrates; starches; cellulosics, such as microcrystalline celluloseor microcrystalline cellulose/sodium carboxymethyl cellulose;inorganics, such as dicalcium phosphate, hydroxyapitite, tricalciumphosphate, talc, or titania; and polyols, such as mannitol, xylitol,sorbitol or cyclodextrin. It should be emphasized that a substrate neednot be a solid material, although often it will be a solid.

Other carriers for use with the present invention include, e.g., starch,modified starch, and starch derivatives, gums, including but not limitedto xanthan gum, alginic acid, other alginates, benitoniite, veegum,agar, guar, locust bean gum, gum arabic, quince psyllium, flax seed,okra gum, arabinoglactin, pectin, tragacanth, scleroglucan, dextran,amylose, amylopectin, dextrin, etc., cross-linked polyvinylpyrrolidone,ion-exchange resins, such as potassium polymethacrylate, carrageenan(and derivatives), gum karaya, biosynthetic gum, etc. Other usefulpolymers include: polycarbonates (linear polyesters of carbonic acid);microporous materials (bisphenol, a microporous poly(vinylchloride),micro-porous polyamides, microporous modacrylic copolymers, microporousstyrene-acrylic and its copolymers); porous polysulfones, halogenatedpoly(vinylidene), polychloroethers, acetal polymers, polyesters preparedby esterification of a dicarboxylic acid or anhydride with an alkylenepolyol, poly(alkylenesulfides), phenolics, polyesters, asymmetric porouspolymers, cross-linked olefin polymers, hydrophilic microporoushomopolymers, copolymers or interpolymers having a reduced bulk density,and other similar materials, poly(urethane), cross-linked chain-extendedpoly(urethane), poly(imides), poly(benzimidazoles), collodion,regenerated proteins, semi-solid cross-linked poly(vinylpyrrolidone).

Additional additives and their levels, and selection of a primarycoating material or materials will depend on the following properties:resistance to dissolution and disintegration in the stomach;impermeability to gastric fluids and drug/carrier/enzyme while in thestomach; ability to dissolve or disintegrate rapidly at the targetintestine site; physical and chemical stability during storage;non-toxicity; easy application as a coating (substrate friendly); andeconomical practicality.

The one or more active agents that are formulated in a self-stablemanner using the present invention may include a wide variety of uses,not just the traditional pharmaceutical agents. Those skilled in the artwill appreciate that any of these compounds may be used in the form oftheir pharmaceutically acceptable salt forms, e.g., carboxylic acids,with counter-ions, e.g., potassium, sodium, calcium; as ioniccombinations with, e.g., resins, polymers, beads, matrices; with sugarsor sugar derivatives, e.g., malate, tannate; amino acids, lipids, oilsor combinations, mixtures and the like. In some embodiments, the presentinventors have found that certain actives may be provided with twodifferent salts, each of which may have a different solubility and/orrelease profile under, e.g., physiologic conditions. In fact, liquidformulation of present invention includes combinations of one or more ofthe following: immediate release, pulsatile release, controlled release,extended release, delayed release, targeted release, or targeted delayedrelease.

Some examples of active ingredients suitable for use in thepharmaceutical formulations and methods of the present invention includehydrophilic, lipophilic, amphiphilic or hydrophobic, and that can besolubilized, dispersed, or partially solubilized and dispersed, on orabout a carrier. For example, the following example may be used for thefollowing active agents:

Example VIII

Active Agent-polistirex 0.33 mg Mannogem ™ EZ 150.00 mg Povidone 10.00mg Aspertame 5.00 mg Coolant 2.67 mg Peppermint Flavor 6.00 mg LakeBlend Lt Green 0.50 mg Talc 30.00 mg Steric acid 5.00 mg

The active agent-carrier combination may be coated further toencapsulate the agent-carrier combination. Alternatively, an activeingredient may also be provided separately from the solid pharmaceuticalcomposition, such as for co-administration. Such active ingredients canbe any compound or mixture of compounds having therapeutic or othervalue when administered to an animal, particularly to a mammal, such asdrugs, nutrients, cosmaceuticals, nutraceuticals, diagnostic agents,nutritional agents, and the like. The active agents of the presentinvention may be found in their native state; however, they willgenerally be provided in the form of a salt. The active agents listedbelow include their isomers, analogs and derivatives.

In one embodiment, the active ingredient agent is hydrophobic.Hydrophobic active ingredients are compounds with little or no watersolubility. Intrinsic water solubilities for hydrophobic activeingredients are generally less than about 15% by weight. Suitablehydrophobic active ingredients are not limited by therapeutic category,and can be, for example, analgesics, anti-inflammatory agents,antihelmimthics, anti-arrhythmic agents, anti-bacterial agents,anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics,anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensiveagents, anti-malariale, anti-migraine agents, anti-muscarinic agents,anti-neoplastic agents, crectile dysfunction improvement agents,immunosuppressants, anti-protozoal agents, anti-thyroid agents,anxiolytic agents, sedatives, hypnotics, neuroleptics, β-Blockers,cardiac inotropic agents, corticosteroids, diuretics, anti-parkinsonianagents, gastro-intestinal agents, histamine receptor antagonists,keratolytics, lipid regulating agents, anti-anginal agents, cox-2inhibitors, leukotriene inhibitors, macrolides, muscle relaxants,nutritional agents, opioid analgesics, protease inhibitors, sexhormones, stimulants, muscle relaxants, anti-osteoporosis agents,anti-obesity agents, cognition enhancers, anti-urinary incontinenceagents, nutritional oils, anti-benign prostate hypertrophy agents,essential fatty acids, non-essential fatty acids, and mixtures thereof.Salts, isomers and derivatives of the above-listed hydrophobic activeingredients may also be used, as well as combinations and mixturesthereof.

Other examples of suitable hydrophobic active ingredients include:acetretin, albendazole, albuterol, aminoglutethimide, amiodarone,amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone,azithromycin, baclofen, beclomethasone, benezepril, benzonatate,betamethasone, bicalutanide, budesonide, bupropion, busulfan,butenafine, calcifediol, calcipotriene, calcitriol, camptothecin,candesartan, capsaicin, carbamezepine, carotenes, celecoxib,cerivastatin, cetirizine, chlorpheniramine, cholecalciferol, cilostazol,cimetidine, cinnarizine, ciprofloxacin, cisapride, clarithromycin,clemastine, clomiphene, clomipramine, clopidogrel, codeine, coenzymeQ10, cyclobenzaprine, cyclosporin, danazol, dantrolene,dexchlorpheniramine, diciofenac, dicoumarol, digoxin,dehydroepiandrosterone, dihydroergotamine, dihydrotachysterol,dirithromycin, donezepil, efavirenz, eposartan, ergocalciferol,ergotamine, essential fatty acid sources, etodolac, etoposide,famotidine, fenofibrate, fentanyl, fexofenadine, finasteride,fluconazole, flurbiprofen, fluvastatin, fosphenytoin, frovatriptan,furazolidone, gabapentin, gemfibrozil, glibenclamide, glipizide,glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen,irbesartan, irinotecan, isosorbide dinitrate, isotretinoin,itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine,lansoprazole, leflunomide, lisinopril, loperamide, loratadine,lovastatin, L-thryroxine, lutein, lycopene, medroxyprogesterone,mifepristone, mefloquine, megestrol acetate, methadone, methoxsalen,metronidazole, miconazole, midazolam, miglitol, minoxidil, mitoxantrone,montelukast, nabumetone, nalbuphine, naratriptan, nelfinavir,nifedipine, nilsolidipine, nilutanide, nitrofurantoin, nizatidine,omeprazole, oprevelkin, oestradiol, oxaprozin, paclitaxel, paracalcitol,paroxetine, pentazocine, pioglitazone, pizofetin, pravastatin,prednisolone, probucol, progesterone, pseudoephedrine, pyridostigmine,rabeprazole, raloxifene, rofecoxib, repaglinide, rifabutine,rifapentine, rimexolone, ritanovir, rizatriptan, rosiglitazone,saquinavir, sertraline, sibutramine, sildenafil citrate, simvastatin,sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen,tamsulosin, targretin, tazarotene, telmisartan, teniposide, terbinafine,terazosin, tetrahydrocannabinol, tiagabine, ticlopidine, tirofibran,tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin,troglitazone, trovafloxacin, ubidecarenone, valsartan, venlafaxine,verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K,zafirlukast, zileuton, zolmitriptan, zolpidem, and zopiclone. Of course,salts, isomers and derivatives of the above-listed hydrophobic activeingredients may also be used, as well combinations and mixtures thereof.

In other embodiments, the active ingredient is hydrophilic, however,combination of hydrophilic, hydrophobic and non-polar agents may also beused. The water solubility for hydrophilic active ingredients isgenerally greater than about 0.1% by weight, and typically greater thanabout 1% by weight. Suitable hydrophilic active ingredients include:analgesics, anti-inflammatory agents, antihelminthics, anti-arrhythmicagents, anti-bacterial agents, anti-viral agents, anti-coagulants,anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents,anti-gout agents, anti-hypertensive agents, anti-malarials,anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents,erectile dysfunction improvement agents, immunosuppressants,anti-protozoal agents, anti-thyroid agents, anxiolytic agents,sedatives, hypnotics, neuroleptics, .beta.-Blockers, cardiac inotropicagents, corticosteroids, diuretics, anti-parkinsonian agents,gastro-intestinal agents, histamine receptor antagonists, keratolytics,lipid regulating agents, anti-anginal agents, cox-2 inhibitors,leukotriene inhibitors, macrolides, muscle relaxants, nutritionalagents, opioid analgesics, protease inhibitors, sex hormones,stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesityagents, cognition enhancers, anti-urinary incontinence agents,nutritional oils, anti-benign prostate hypertrophy agents, essentialfatty acids, non-essential fatty acids, and mixtures thereof

Other hydrophilic active ingredients include: a cytokine, apeptidomimetic, a peptide, a protein, a toxoid, a serum, an antibody, avaccine, a nucleoside, a nucleotide, a portion of genetic material, anucleic acid, or a mixture thereof. Other examples of suitablehydrophilic active ingredients include: acarbose; acyclovir; acetylcysteine; acetylcholine chloride; alatrofloxacin; alendronate;aglucerase; amantadine hydrochloride; ambenomium; amifostine; amiloridehydrochloride; aminocaproic acid; amphotericin B; antihemophilic factor(human), antihemophilic factor (porcine); antihemophilic factor(recombinant), aprotinin; asparaginase; atenolol; atracurium besylate;atropine; azithromycin; aztreonam; BCG vaccine; bacitracin; becalermin;belladona; bepridil hydrochloride; bleomnycin sulfate; calcitonin human;calcitonin salmon; carboplatin; capecitabine; capreomycin sulfate;cefamandole nafate; cefazolin sodium; cefepime hydrochloride; cefixime;cefonicid sodium; cefoperazone; cefotetan disodium; cefotaxime;cefoxitin sodium; ceftizoxime; ceftriaxone; cefuroxime axetil;cephalexin; cephapirin sodium; cholera vaccine; chorionic gonadotropin;cidofovir; cisplatin; cladribine; clidinium bromide; clindamycin andclindamycin derivatives; ciprofloxacin; clodronate; colistimethatesodium; colistin sulfate; corticotropin; cosyntropin; cromolyn sodium;cytarabine; dalteparin sodium; danaparoid; desferrioxamine; denileukindiflitox; desmopressin; diatrizoate meglumine and diatrizoate sodium;dicyclomine; didanosine; dirithromycin; dopamine hydrochloride; domasealpha; doxacurium chloride; doxorubicin; etidronate disodium;enalaprilat; enkephalin; enoxaparin; enoxaprin sodium; ephedrine;epinephrine; epoetin alpha; erythromycin; esmolol hydrochloride; factorIX; famciclovir, fludarabine; fluoxetine; foscamet sodium; ganciclovir,granulocyte colony stimulating factor, granulocyte-macrophagestimulating factor, growth hormones—recombinant human; growthhormone—bovine; gentamycin; glucagon; glycopyrolate; gonadotropinreleasing hormone and synthetic analogs thereof; GnRH; gonadorelin;grepafloxacin; haemophilus B conjugate vaccine; Hepatitis A virusvaccine inactivated; Hepatitis B virus vaccine inactivated; heparinsodium; indinavir sulfate; influenza virus vaccine; interleukin-2;interleukin-3; insulin-human, insulin lispro; insulin procine; insulinNPH; insulin aspart; insulin glargine; insulin detemir; interferonalpha; interferon beta; ipratropium bromide; ifosfamide; Japaneseencephalitis virus vaccine; lamivudine; leucovorin calcium; leuprolideacetate, levofloxacin; lincomycin and lincomycin derivatives; lobucavir;lomefloxacin; loracarbef; mannitol; is measles virus vaccine;meningococcal vaccine; menotropins; mepenzolate bromide; mesalamine;methenamine; methotrexate; methscopolamine; metformin hydrochloride;metoprolol; mezocillin sodium; mivacurium chloride; mumps viral vaccine;nedocromil sodium; neostigmine bromide; neostigmine methyl sulfate;neurontin; norfloxacin; octreotide acetate; ofloxacin; olpadronate;oxytocin; pamidronate disodium; pancuronium bromide; paroxetine;perfloxacin; pentamidine isethionate; pentostatin; pentoxifylline;periciclovir, pentagastrin; pentholamine mesylate; phenylalanine;physostigmine salicylate; plague vaccine; piperacillin sodium; plateletderived growth factor-human; pneumococcal vaccine polyvalent; poliovirusvaccine inactivated; poliovirus vaccine live (OPV); polymyxin B sulfate;pralidoxime chloride; pramlintide, pregabalin; propafenone;propenthaline bromide; pyridostigmine bromide; rabies vaccine;residronate; ribavarin; rimantadine hydrochloride; rotavirus vaccine;salmeterol xinafoate; sinealide; small pox vaccine; solatol;somatostatin; sparfloxacin; spectinomycin; stavudine; streptokinase;streptozocin; suxamethonium chloride; tacrine hydrochloride; terbutalinesulfate; thiopeta; ticarcillin; tiludronate; timolol; tissue typeplasminogen activator, TNFR:Fc; TNK-tPA; trandolapril; trimetrexategluconate; trospectinomycin; trovafloxacin; tubocurarine chloride; tumornecrosis factor; typhoid vaccine live; urea; urokinase; vancomycin;valacyclovir, valsartan; varicella virus vaccine live; vasopressin andvasopressin derivatives; vecuronium bromide; vinblastine; vincristine;vinorelbine; vitamin B12; warfarin sodium; yellow fever vaccine;zalcitabine; zanamivir, zolendronate; zidovudine; pharmaceuticallyacceptable salts, isomers and derivatives thereof; and mixtures thereof.

A wide variety of therapeutically active agents can be used inconjunction with the present invention. The therapeutically activeagents (e.g. pharmaceutical agents) which may be used in thecompositions of the present invention include both water soluble andwater insoluble drugs. Examples of such therapeutically active agentsinclude antihistamines (e.g., dimenhydrinate, diphenhydramine,chlorpheniramine and dexchlorpheniramine maleate), analgesics (e.g.,aspirin, codeine, morphine, dihydromorphone, oxycodone, etc.),non-steroidal anti-inflammatory agents (e.g., naproxyn, diclofenac,indomethacin, ibuprofen, sulindac), anti-emetics (e.g., metoclopramide),anti-epileptics (e.g., phenytoin, meprobamate and nitrezepam),vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardirine),anti-tussive agents and expectorants (e.g., codeine phosphate),anti-asthmatics (e.g. theophylline), antacids, anti-spasmodics (e.g.,atropine, scopolamine), antidiabetics (e.g., insulin), diuretics (e.g.,ethacrynic acid, bendrofluazide), anti-thypotensives (e.g., propranolol,clonidine), antihypertensives (e.g, clonidine, methyldopa),bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone,triamcinolone, prednisone), antibiotics (e.g., tetracycline),antihemorrhoidals, hypnotics, psycho-tropics, antidiarrheals,mucolytics, sedatives, decongestants, laxatives, vitamins, stimulants(including appetite suppressants such as phenylpropanolamine), as wellas salts, hydrates, and solvates of the same. The above list is notmeant to be exclusive.

In certain embodiments, the therapeutically active agent includehydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine,morphine, buprenorphine, salts, hydrates and solvates of any of theforegoing, mixtures of any of the foregoing, and the like. In otherembodiments, the active agent is a locally active therapeutic agent andthe environment of use may be, e.g., the gastrointestinal tract, or bodycavities such as the oral cavity, periodontal pockets, surgical wounds,the rectum or vagina. The liquid formulations of the present inventionmay be provided orally, topically, subcutaneously, intramuscularly,intraperitoneally, intraocularly, intraossealy, nasally, urethrally,mucosally, vaginally, rectally, intradurally, epidurally and the like.The liquid formulation of the present invention may also be provided asa mist, e.g., to the deep lung (alveolarly).

Locally active pharmaceutical agents of use with the present inventioninclude antifungal agents (e.g., amphotericin B, clotrimazole, nystatin,ketoconazole, miconazol, etc.), antibiotic agents (penicillins,cephalosporins, erythromycin, tetracycline, aminoglycosides, etc.),antiviral agents (e.g, acyclovir, idoxuridine, etc.), breath fresheners(e.g. chlorophyll), antitussive agents (e.g., dextromethorphanhydrochloride), anti-cariogenic compounds (e.g. metallic salts offluoride, sodium monofluorophosphate, stannous fluoride, aminefluorides), analgesic agents (e.g., methylsalicylate, salicylic acid,etc.), local anesthetics (e.g., benzocaine), oral anti-septics (e.g.,chlorhexidine and salts thereof, hexylresorcinol, dequalinium chloride,cetylpyridinium chloride), anti-flammatory agents (e.g., dexamethasone,betamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone,etc.), hormonal agents (oestriol), antiplaque agents (e.g, chlorhexidineand salts thereof, octenidine, and mixtures of thymol, menthol,methysalicylate, eucalyptol), acidity reducing agents (e.g., bufferingagents such as potassium phosphate dibasic, calcium carbonate, sodiumbicarbonate, sodium and potassium hydroxide, etc.), and toothdesensitizers (e.g., potassium nitrate). This list is not meant to beexclusive.

The examples herein include pharmaceutically active compounds useful inthe practice of the present invention, e.g., antihistamines,decongestants, antitussives and/or expectorants. Other actives for usewith the present invention include, but are not limited to:non-steroidal anti-inflammatory drugs (NSAIDs) and other analgesic drugssuch as acetominophen and phenacetin. These materials are incorporatedinto the immediate or controlled release formulations of the inventionin amounts governed by the desired release characteristics of thematerial in such excipient base and such that conventional dosagescomply with applicable federal Food and Drug Administration (FDA) orother regulations.

Decongestants useful with the present invention (along with a salt form)are phenylephrine (bitartrate, tannate, HBr, HCl), phenylpropanolamine(HCl) and pseudoephedrine (HCl). Furthermore, a number of herbal and/ornatural decongestants are known in the art, all of which may be usedwith the present invention.

Expectorants for use with the present invention include, e.g.,guaifenesin, terpin hydrate, (glyceryl guaiacolate), potassium (iodide,citrate) and potassium guaicolsulfonate. Other expectorants, whetherindividual ingredients or combinations of ingredients may be used withthe present invention. Furthermore, a number of herbal and/or naturalexpectorants are known in the art, all of which may be used with thepresent invention.

Examples of antihistamines for use with the present invention (e.g., insalt form) are chlorpheniramine (maleate), brompheniramine (maleate),dexchlorpheniramine (maleate), dexbrompheniramine (maleate),triprolidine (HCl), diphenhydramine (HCl), doxylamine (succinate),tripelennamine (HCl), cyproheptatine (HCl), bromodiphenhydramine (HCl),phenindamine (tartrate), pyrilamine (maleate, tannate) and azatadine(maleate). Antitussives that may be used with the present invention(with salt form) include: caramiphen (edisylate), dextromethorphan (HBr)and codeine (phosphate, sulfate). A number of herbal and/or naturalantihistamines are known in the art, all of which may be used with thepresent invention.

Other actives may also be included with the present invention, e.g.,non-steroidal anti-inflammatory drugs (NSAIDs) such as propionic acidderivatives; acetic acid derivatives; fenamic acid derivatives;biphenylcarboxylic acid derivatives; and oxicams. Examples of propionicacid derivatives include: ibuprofen, naproxen, ketoprofen, flurbiprofen,fenoprofen, suprofen, fenbufen, and fluprofen may be mentioned aspreferred compounds. Acetic acid derivatives derivatives include:tolmetin sodium, zomepirac, sulindac and indomethacin. Fenamic acidderivatives derivatives include: mefenamic acid and meclofenamatesodium. Diflunisal and flufenisal are biphenylcarboxylic acidderivatives, while oxicams include piroxicam, sudoxicam and isoxicam.Other analgesics for use with the present invention includeacetominophen and phenacetin. Naproxen may be present in amounts ofabout 50 to about 250 milligrams per dose, however, naproxen may be usedin amounts of between about 100 and about 150 milligrams per liquiddose.

Phenylephrine may be present in amounts of between about 15 and about 60milligrams per liquid dose. Phenylephrine is generally in amounts ofabout 5 to about 30 milligrams per liquid dose, with half or less ofthat amount used in a pediatric form of the formulation. In one exampleof the present invention, phenylephrine is provided in the amount ofabout 15 mg for extended release. Phenylephrine hydrochloride is anorally effective nasal decongestant. Chemically it is(S)-3-hydroxy-α[(methylamino) methyl]benzenemethanol hydrochloride.Phenylepherine is a synthetic, optically active sympathomimetic aminethat has one hydroxyl group on the benzene ring. The hydroxyl group isplaced in the position meta to the aliphatic side chain. The metaposition affords optimal activity and phenylepherine (neo-synephrine)replaced an older preparation, synephrine, in which the hydroxyl was inthe para position.

Phenylephrine hydrochloride is available in the form of the levorotatoryisomer, a white, odorless, non-hygroscopic, crystalline compoundpossessing a bitter taste. Phenylephrine hydrochloride has a meltingpoint of 140-145 degrees C and is freely soluble in water and alcohol.Decongestant compounds in the form of their free bases as well as theirsalts, e.g., hydrochloride, citrate, maleate, tannate, etc., are wellknown.

Dextromethorphan may be present in amounts of between about 5 and about20 milligrams per liquid dose, with a general range of about 10 to about15 milligrams. Brompheniramine may be present in amounts of betweenabout 0.5 and about 4.0 milligrams per liquid dose with a general rangeof about 2.0 milligrams per liquid dose. Half or less of that amount maybe used in a pediatric form of the formulation.

The present invention may also include chlorpheniramine, which is anantihistamine used to relieve, e.g., allergic rhinitis (seasonalallergy). The symptoms of allergic rhinitis include: sneezing, runnynose, itching, and watery eyes. Chlorpheniramine may also be used totreat immediate allergic reactions. Chlorpheniramine may be providedalone and in combination with other prescription or nonprescriptiondrugs, e.g., to treat symptoms of allergy, colds, and upper respiratoryinfections.

The pharmaceutical composition and/or the solid carrier particles can becoated with one or more enteric coatings, seal coatings, film coatings,barrier coatings, compress coatings, fast disintegrating coatings, orenzyme degradable coatings. Multiple coatings may be applied for desiredperformance. Further, some actives may be provided for slow release,pulsatile release, controlled release, extended release, delayedrelease, targeted release, synchronized release, or targeted delayedrelease. For release/absorption control, solid carriers can be made ofvarious component types and levels or thicknesses of coats, with orwithout an active ingredient. Such diverse solid carriers can be blendedin a dosage form to achieve a desired performance. The compositions maybe formulated for oral, nasal, buccal, ocular, urethral, transmucosal,vaginal, topical or rectal delivery, although oral delivery is usedmostly.

The present invention may also contain a plasticizer and possibly othercoating excipients such as colorants, talc, and/or magnesium stearate,which are well known in the art. Suitable plasticizers include: triethylcitrate (citroflex 2), triacetin (glyceryl triacetate), acetyl triethylcitrate, carbowax 400 (polyethylene glycol 400), diethyl phthalate,tributyl citrate, acetylated monoglycerides, glycerol, fatty acidesters, propylene glycol, and dibutyl phthalate. In particular, anioniccarboxylic acrylic polymers usually will contain about 5-25% by weightof a plasticizer, especially dibutyl phthalate, polyethylene glycol,triethyl citrate and triacetin. Conventional coating techniques such asspray or pan coating are employed to apply coatings. The coatingthickness must be sufficient to ensure that the oral dosage form remainsintact until the desired site of topical delivery in the lowerintestinal tract is reached.

It should be appreciated that there is considerable overlap between theabove-listed additives in common usage, since a given additive is oftenclassified differently by different practitioners in the field, or iscommonly used for any of several different functions. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in compositionsof the present invention. The amounts of such additives may be readilydetermined by one skilled in the art, according to the particularproperties desired.

Additives may be include, e.g., pre-mixed propylene glycol, glycerin,citric acid, sodium benzoate, povidone (kollidon 30), sorbitol solutionand the like. Flavorants, sweeteners, preservatives, bitter maskingagent, thickeners and the like may also be added to the blender. In oneexample, the flavorants may be lemon, bubble gum, grape, wild cherry orother flavors, with sweeteners including saccharin or honey. Inaddition, a glycerin solution may be added in addition to water, e.g.,double deionized water.

In addition the present invention may be in the form of a chewing gumformulation based on natural rubber have been widely used in thepharmaceutical industry. The advantages are the pleasant and populardosage form and rapid, sublingual absorption of an active ingredient.When in the form of a chewing gum the present invention may includewaxes, such as, for example, beeswax, solid paraffin, ozocerite,polyols, cellulose esters, pharmaceutically active materials, flavoringagents, sweeteners, colorants, stearic acid, calcium stearate, magnesiumstearate, solubilizers, chelating agents, surface stabilizer, additives,or similar substances, may be used to ensure a longer chewing time, haveproven particularly advantageous with regard to the chewability.

In yet another embodiment, the formulation may be a combination of asoft-gel or liquid interior coated with a more firm exterior. Forexample, certain agents may be provided for immediate release in athixotropic gel in the interior of a gel or chewing-gum-like exterior.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents which are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results would be achieved. All suchsimilar substitutes and modifications apparent to those skilled in theart are deemed to be within the spirit, scope and concept of theinvention as defined by the appended claims.

What is claimed is:
 1. A taste-masked pharmaceutical compositioncomprising: a drug-resin complex and a highly compressible, free-flowingpharmaceutical excipient, wherein the resin is present in an amounteffective to reduce the taste of the drug in the drug resin complex bymore than about 15 percent relative to an otherwise identicalpharmaceutical composition without the resin; and wherein the highlycompressible, free-flowing pharmaceutical excipient aids release of thedrug-resin complex in the mouth.
 2. The composition of claim 1, whereinthe composition comprises a chewable tablet, a solid, a dissolvable ordisintegrating tablet, a liquid, a gel, a tab, a capsule, a powder, alotion, a cream, a gum, a lozenge and combinations thereof.
 3. Thecomposition of claim 1, wherein the drug in the drug-resin complexcomprises dextromethorphan, codeine, morphine, hydrocodone, hyoscyamine,moguisteine, pseudoephedrine, chlorpheniramine, phenylpropanolamine,pharmaceutically acceptable salts of the same and combinations thereof.4. The composition of claim 1, wherein the pharmaceutical composition issuitable for oral administration.
 5. The composition of claim 1, furthercomprising one or more flavorants, sweeteners, coolants, dyes, orcombinations and mixtures thereof.
 6. The composition of claim 1,further comprising one or more excipients, one or more binders orcombinations and mixtures thereof.
 7. The pharmaceutical of claim 1,wherein the drug-resin complex comprises polistirex, polyacrilex andcombinations thereof.
 8. The pharmaceutical of claim 1, wherein thedrug-resin complex comprises pseudoephedrine polistirex andchlorpheniramine polyacrilex.
 9. The pharmaceutical of claim 1, whereinthe resin in the drug-resin complex comprises one or more cationicexchange resins.
 10. The pharmaceutical of claim 1, wherein thedrug-resin complex comprises a divinylbenzene sulfonic acid cationicexchange resin.
 11. The pharmaceutical of claim 1, wherein thecomposition comprises a hardness of between about 5 and about 15 kPa.12. The pharmaceutical of claim 1, wherein the composition has at leastabout 20 percent better mouth-feel.
 13. The pharmaceutical of claim 1,wherein the drug-resin complex comprises a diffusion barrier coating.14. The pharmaceutical of claim 13, wherein the diffusion barriercoating is a time release coating.
 15. A rapidly dissolving ordisintegrating, taste-masked pharmaceutical composition comprising: adrug-resin complex and a compressible, free-flowing, pharmaceutical,taste-masking excipient, wherein the resin is present in an amounteffective to reduce the taste of the drug in the drug resin complexrelative to an otherwise identical pharmaceutical composition withoutthe resin; and wherein the highly compressible, free-flowingpharmaceutical excipient causes release of the drug-resin complex in themouth.
 16. The pharmaceutical of claim 15, wherein the drug-resincomplex comprises polistirex, polyacrilex and combinations thereof. 17.The pharmaceutical of claim 15, wherein the drug-resin complex comprisespseudoephedrine polistirex and chlorpheniramine polyacrilex.
 18. Achewable tablet comprising: a pharmaceutically active drug-resincomplex, whereby the pharmaceutically active ingredient is slowlyreleased when the tablet is chewed, the tablet becoming thixotropic whenchewed but not fully dissociating for at least 30 seconds when chewed,and the tablet slowly dissociates when the tablet is chewed, so as tocompletely dissociate thereafter once swallowed; and one or moreamorphous sugars.
 19. The pharmaceutical of claim 18, wherein thepharmaceutically active drug-resin complex comprises polistirex,polyacrilex and combinations thereof.
 20. The pharmaceutical of claim18, wherein the pharmaceutically active drug-resin complex comprisespseudoephedrine polistirex and chlorpheniramine polyacrilex.
 21. Thecomposition of claim 18, further comprising one or more flavorants,sweeteners, coolants, dyes, or combinations and mixtures thereof. 22.The composition of claim 18, further comprising one or more excipients,one or more binders or combinations and mixtures thereof.
 23. Ataste-masked chewable pseudoephedrine and chlorpheniraminepharmaceutical composition comprising: a pseudoephedrine-resin complex;a chlorpheniramine-resin complex; one or more amorphous sugars; and acompressible, free-flowing, pharmaceutical, taste-masking excipient,wherein the highly compressible, free-flowing pharmaceutical excipientaids release of the drug-resin complex in the mouth.
 24. Thepharmaceutical of claim 23, wherein the pseudoephedrine-resin complex,chlorpheniramine-resin complex or both comprise a polistirex resin, apolyacrilex resin and combinations thereof.
 25. A rapidly dissolving,taste-masked hyoscyamine pharmaceutical composition comprising: ahyoscyamine-resin complex, whereby the hyoscyamine is released when thetablet disintegrates; and one or more amorphous sugars; and acompressible, free-flowing, pharmaceutical, taste-masking excipient. 26.The composition of claim 25, further comprising one or more flavorants,sweeteners, coolants, dyes, or combinations and mixtures thereof. 27.The composition of claim 25, further comprising one or more excipients,one or more binders or combinations and mixtures thereof.
 28. Ataste-masked chewable pseudoephedrine and chiorpheniraminepharmaceutical composition comprising: a pseudoephedrine-resin complex;a chlorpheniramine-resin complex; one or more amorphous sugars; and acompressible, free-flowing, pharmaceutical, taste-masking excipient,whereby the pseudoephedrine and the chlorpheniramine are slowly releasedwhen the composition is chewed, the composition becoming thixotropicwhen chewed but not fully dissociating for at least 10 seconds whenchewed, and the composition slowly dissociates when the composition ischewed, so as to fully dissociate after the mixture is swallowed.